Patients with well-documented chronic hepatitis C are being evaluated to determine the long-term natural history and immune pathogenesis of this disease and to evaluate therapies, particularly in patients who fail to respond to conventional therapy. The current, optimal therapy for chronic hepatitis C is the combination of peginterferon and ribavirin given for 24 to 48 weeks. This regimen induces a sustained clearance of HCV RNA from serum and improvement in serum aminotransferases and the underlying the liver disease in approximately 55% of patients. For patients who do not become HCV RNA negative with therapy, there are few other options. Current studies in the Liver Diseases Section, NIDDK focus upon these patients who fail to respond to the standard therapy of hepatitis C. In two studies, the effects of ribavirin monotherapy are being evaluated. Patients who fail to respond to the combination of interferon and ribavirin are randomized to receive either placebo or ribavirin monotherapy for one year. Among 108 patients treated with combination therapy, 50 failed to respond with clearance of virus of whom 34 were randomized to receive placebo (n=17) or ribavirin (n=17). After a year of treatment, medical evaluation and liver biopsies revealed improvements in serum aminotransferase levels and in liver biopsy evidence of necroinflammation with ribavirin therapy (p<.01), but no change in fibrosis. In a follow up study, 28 patients have been treated with ribavirin long-term and liver biopsies after two to four years in the first 14 patients show no regression of fibrosis scores. These studies will be continued until at least adequate numbers of patients have been treated for four years or more and have repeat liver biopsy histology. A second approach to treatment of non-responder patients is maintenance therapy with interferon. The Liver Diseases Section is participating in a large, multicenter, randomized controlled trial known as HALT-C, which focuses on long-term therapy of chronic hepatitis C with peginterferon. In this trial, patients are first treated with peginterferon and ribavirin for 24 weeks; patients who do not become HCV RNA negative are then randomized to receive long-term peginterferon therapy or no treatment, being followed at 3 month intervals and liver biopsy every two years. This study is a multicenter U.S. trial sponsored by NIDDK which is being conducted in 10 centers including the Clinical Center of the NIH. A total of 1000 patients have been randomized into this study, including 55 at the NIH Clinical Center. At least 10 patients have now undergone the two year follow up evaluation and liver biopsy. Results of this study will define the role of chronic therapy with peginterferon in chronic hepatitis C. A third approach to therapy of non-responder patients is the use of new antiviral agents. The Liver Diseases Section has evaluated gamma interferon, a T cell cytokine that has antiviral activity against HCV in the replicon tissue culture system. Eleven patients who failed to respond to combination therapy were treated with a 4-week course of three different doses of gamma interferon while being monitored for changes in HCV viral levels. HCV RNA levels did not change at any time during therapy with any of the three doses. Serum aminotransferases were also unchanged. As a result of these studies, we have discontinued evaluation of gamma interferon. Two other clinical studies are being conducted in chronic hepatitis C: one focusing on patients with HCV genotype 1 and one on patients with genotypes 2 and 3. In patients with genotype 1, careful viral kinetics are being performed during therapy in up to 25 patients treated with peginterferon and ribavirin, 25 patients treated with peginterferon alone, and 25 patients with both hepatitis C and end-stage renal disease treated with peginterferon alone. To date 24 patients have been enrolled. The viral kinetics, side effects and outcome of treatment will be compared in the three groups. These studies will define the role of ribavirin in decreasing HCV RNA levels and whether the presence of renal disease alters viral kinetic responses. Finally a study of therapy in patients with genotypes 2 and 3 will focus on use of an abbreviated course of treatment and low doses of both peginterferon (half dose) and ribavirin (800 mg instead of 1000-1200 mg daily). This study will attempt to define whether lower and better tolerated doses of peginterferon and ribavirin will be adequate to treat genotype 2 and 3 HCV infections (which typically have a high rate of response to therapy (75-80%). Finally, the Liver Diseases Section participates in long-term natural history studies of chronic hepatitis C in collaboration with the Division of Transfusion Medicine. Volunteer blood donors found to have chronic hepatitis C are followed at regular intervals and undergo liver biopsy at 5 year intervals. This study will help define the natural history of hepatitis C and the clinical correlates that predict disease progression.